title: Endogenous prostaglandin D2 and its metabolites protect the heart against ischemia-reperfusion injury by activating Nrf2.
abstract: We recently demonstrated that glucocorticoids markedly upregulate the expression of cyclooxygenase-2 in cardiomyocytes and protect hearts from ischemia-reperfusion (I/R) injury by activating lipocalin-type prostaglandin D (PGD) synthase (L-PGDS)-derived PGD(2) biosynthesis. We examined a downstream mechanism of cardioprotection elicited by PGD(2) biosynthesis. Acute PGD(2) treatment did not protect hearts against I/R injury. We then speculated that PGD(2) and its metabolite 15-deoxy-Δ12,14-PGJ(2) activate gene expression networks to mediate the glucocorticoid-mediated cardioprotection. Using an unbiased approach, we identified that glucocorticoids induce a number of well-known erythroid-derived 2-like 2 (Nrf2) target genes in the heart in an L-PGDS-dependent manner and that the cardioprotective effect of glucocorticoids against I/R injury was not seen in Nrf2-knockout hearts. We showed relatively low expression of PGD(2) receptors (ie, DP1 and DP2) in the heart but abundant expression of PGF(2α) receptor (FP), which binds PGF(2α) and PGD(2) with equal affinity. Glucocorticoids also failed to induce the expression of L-PGDS-dependent Nrf2 target genes in FP-knockout hearts. PGD(2) acted through its metabolite 15-deoxy-Δ12,14-PGJ(2) in the heart as evidenced by the glucocorticoid-mediated activation of peroxisome proliferator-activated receptor-γ. In turn, glucocorticoids failed to induce the expression of L-PGDS-dependent Nrf2 target genes in hearts pretreated with peroxisome proliferator-activated receptor-γ antagonist GW9662, and glucocorticoid-mediated cardioprotection against I/R injury was compromised in FP-knockout mice and GW9662-treated mice. In conclusion, PGD(2) protects heart against I/R injury by activating Nrf2 predominantly via FP receptor. In addition, we propose activation of peroxisome proliferator-activated receptor-γ by the dehydrated metabolite of PGD(2) (15-deoxy-Δ12,14-PGJ(2)) as another mechanism by which glucocorticoids induce cardioprotection.
authors.affiliation: Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan. msano@a8.keio.jp.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Katsumata
authors.forename: Ken
authors.initials: K
authors.lastname: Shinmura
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sugiura
authors.forename: Shugo
authors.initials: S
authors.lastname: Tohyama
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsuhashi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ito
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Yan
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ito
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Yuasa
authors.forename: Masaki
authors.initials: M
authors.lastname: Ieda
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D054834:Lipocalins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000378:metabolism
chemical_list: C477819:15-deoxyprostaglandin J2; D005938:Glucocorticoids; D054834:Lipocalins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D047495:PPAR gamma; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; D003907:Dexamethasone; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2
keywords: 15-deoxyprostaglandin J2; Nrf2; PPAR gamma; oxidative stress; prostaglandin D2; prostaglandin F2α receptor